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PA27.{11,15} | Vascular Diseases & Thrombotic Microangiopathies — SDL Guide (Part 2)

Renal Artery Stenosis and Renovascular Hypertension

Diagram showing renal artery stenosis reducing kidney perfusion, activating RAAS, and causing renovascular hypertension, with comparison of atherosclerotic stenosis and fibromuscular dysplasia. — **Panel A:** Abdominal aorta, renal arteries, proximal renal artery stenosis, affected kidney, contralateral kidney, reduced perfusion pressure, juxtaglomerular apparatus, renin release, systemic hypertension.. **Panel B:** Atherosclerotic renal artery stenosis: ostial/proximal 2 cm lesion, irregular concentric plaque, older male smoker association; Fibromuscular dysplasia: mid-to-distal renal artery, string-of-beads appearance, young or middle-aged female association.. **Panel C:** Reduced renal perfusion pressure, juxtaglomerular cells, renin, angiotensin II, systemic vasoconstriction, aldosterone, sodium and water retention, increased blood pressure..

Renal artery stenosis (RAS) reduces perfusion pressure to one or both kidneys, activating the RAAS and producing renovascular hypertension — a potentially curable secondary form of hypertension.

Two aetiological types:

Feature	Atherosclerotic RAS	Fibromuscular dysplasia (FMD)
Age/sex	Older males, smokers	Young/middle-aged females
Location	Proximal (ostium/proximal 2 cm)	Middle and distal renal artery
Angiographic appearance	Concentric plaque, irregular stenosis	String-of-beads (alternating stenoses and aneurysms)
Laterality	Usually unilateral	Usually unilateral; bilateral in 30%

Pathogenesis of hypertension:
Reduced renal perfusion → juxtaglomerular cells sense low pressure → renin release → Ang II → systemic vasoconstriction + aldosterone → BP rises. The contralateral normal kidney is suppressed — exposed to high BP but normal perfusion-pressure RAAS dynamics.

Renal morphology:
• Ipsilateral kidney: ischaemic nephropathy — atrophic, small, with tubular atrophy, interstitial fibrosis, and juxtaglomerular cell hyperplasia
• If untreated → permanent renal atrophy

Diagnosis: captopril-enhanced isotope renogram, Doppler ultrasound, CT/MR angiography.
Treatment: angioplasty ± stent (FMD responds excellently); ACE inhibitor is CONTRAINDICATED in bilateral stenosis → causes acute renal failure by removing the efferent arteriolar tone that maintains GFR.

Thrombotic Microangiopathy: Unifying Concept

Diagram showing how endothelial injury from several triggers causes platelet-fibrin microthrombi, RBC fragmentation into schistocytes, thrombocytopenia, AKI, and characteristic renal TMA morphology. — **Panel A:** Endothelial injury, Shiga toxin, ADAMTS13 deficiency, complement activation, platelet-fibrin microthrombus, capillary lumen, injured endothelium, fibrin strands, consumed platelets.. **Panel B:** RBC shearing, fibrin strands, microangiopathic haemolytic anaemia, schistocytes, helmet cells, fragmented RBCs.. **Panel C:** Glomerular capillary thrombi, afferent arteriole thrombus, interlobular artery involvement, bloodless glomerular capillary loops, fragmented RBCs in capillaries, acute kidney injury, no immune deposits on immunofluorescence..

Thrombotic microangiopathy (TMA) is not a single disease but a pathological syndrome defined by:

1. Endothelial injury in small vessels (arterioles and capillaries)
2. Formation of platelet-fibrin microthrombi in vessel lumina
3. Downstream consequences:
- Microangiopathic haemolytic anaemia (MAHA) — RBCs sheared by fibrin strands → schistocytes (helmet cells, fragmented RBCs) on blood film
- Thrombocytopenia — platelets consumed in thrombi
- Acute kidney injury (AKI) — glomerular and arteriolar microthrombi → ischaemia

Shared renal morphology (regardless of cause):
• Fibrin/platelet thrombi in glomerular capillaries, afferent arterioles, interlobular arteries
• Glomerular capillary wall thickening (bloodless glomeruli — capillaries occluded, no blood)
• Schistocytes and fragmented RBCs visible in glomerular capillaries on biopsy
• No immune deposits on immunofluorescence (distinguishes TMA from immune-mediated GN)

TMA causes — the unifying mechanism operates in:
• HUS (typical and atypical)
• TTP
• DIC
• Scleroderma renal crisis
• Malignant hypertension (overlap)
• Antiphospholipid syndrome
• Pregnancy-associated (HELLP, eclampsia)

Diagram showing Shiga toxin, complement activation, and ADAMTS13 deficiency causing endothelial injury, platelet-fibrin microthrombi, schistocytes, platelet consumption, and acute kidney injury in TMA. — **Panel A:** Renal capillary cutaway showing Shiga toxin, complement activation, and ADAMTS13 deficiency arrows converging on endothelial injury with platelet-fibrin microthrombus formation and luminal narrowing.. **Panel B:** Mechanical fragmentation of red blood cells by fibrin strands, producing schistocytes.. **Panel C:** Platelet incorporation into microthrombi causing platelet consumption and thrombocytopenia.. **Panel D:** Renal consequence of TMA showing acute kidney injury with oliguria and raised creatinine..

SELF-CHECK

A 7-year-old presents with bloody diarrhoea followed by oliguria, pallor, and bruising. Blood film shows fragmented red blood cells. Platelets 22,000/μL, haemoglobin 7.2 g/dL, creatinine elevated. What is the mechanism of anaemia in this condition?

A. Autoimmune IgG against red cell antigens (warm AIHA)

B. Bone marrow suppression by bacterial exotoxin

C. Mechanical fragmentation of RBCs by intravascular fibrin strands

D. Direct complement-mediated lysis of red blood cells

Reveal Answer

Answer: C. Mechanical fragmentation of RBCs by intravascular fibrin strands

This is classic HUS (typical/childhood form) following Shiga-toxin-producing E. coli O157:H7. The anaemia is microangiopathic — fibrin strands deposited in glomerular capillaries shear passing RBCs into schistocytes (fragmented cells). This is mechanical intravascular haemolysis: Coombs-negative (not immune), no complement-mediated lysis (as in PNH). Bone marrow suppression does not produce schistocytes on blood film.

Haemolytic Uraemic Syndrome (HUS)

A four-panel medical diagram compares typical and atypical HUS, showing Shiga toxin and complement-mediated endothelial injury leading to thrombotic microangiopathy, renal morphology, and the clinical triad. — **Panel A:** Typical D+ HUS pathogenesis: undercooked beef or contaminated food, E. coli O157:H7 or Shigella dysenteriae type 1, Shiga toxin Stx1/Stx2, bloody diarrhoea, systemic absorption, Gb3 receptor, glomerular endothelial cell, mesangial cell, endothelial injury, thrombotic microangiopathy.. **Panel B:** Typical HUS versus atypical HUS comparison: Shiga toxin, children under 5 years, diarrhoeal prodrome, Gb3-mediated endothelial injury, supportive care and recovery; complement factor H, factor I, MCP/CD46, C3/CFB mutations, anti-CFH antibodies, no diarrhoeal prodrome, relapsing course, ESRD risk, eculizumab anti-C5 therapy.. **Panel C:** Renal morphology: glomerular fibrin thrombi, mesangiolysis, capillary wall double contour, subendothelial expansion, lobular pattern, arteriolar fibrinoid necrosis, onion-skin arteriolar change.. **Panel D:** Clinical triad: microangiopathic haemolytic anaemia with schistocytes, thrombocytopenia with reduced platelets, acute kidney injury with oliguria, haematuria, and hypertension..

Typical (Childhood / D+ HUS):

Cause: Shiga toxin (Stx1 or Stx2) produced by E. coli O157:H7 (haemorrhagic colitis, undercooked beef) or Shigella dysenteriae type 1
Epidemiology: Children under 5; preceded by bloody diarrhoea (D+HUS = diarrhoea-associated)
Pathogenesis: Stx absorbed from gut → systemic circulation → binds Gb3 receptor on glomerular endothelial cells and mesangial cells (Gb3 highly expressed in child kidneys — explains age predilection) → endothelial activation/injury → TMA
Clinical triad: MAHA + thrombocytopenia + AKI → oliguria, haematuria, hypertension
Prognosis: ~90% recover with supportive care; 5-10% progress to CKD

Atypical (aHUS / D- HUS):

Cause: Complement pathway dysregulation — mutations in complement factor H (CFH), factor I, membrane cofactor protein (MCP/CD46), or gain-of-function C3/CFB mutations; also anti-CFH antibodies
Mechanism: Uncontrolled alternative complement activation → endothelial injury → TMA (no diarrhoeal prodrome)
Course: More severe, relapsing; 50% progress to ESRD
Treatment: Eculizumab (anti-C5 monoclonal antibody — blocks terminal complement activation) — transformative therapy for aHUS

Key renal morphology (both HUS types):
• Glomerular: fibrin thrombi, mesangiolysis, capillary wall double-contour (subendothelial expansion), lobular pattern
• Arteriolar: fibrinoid necrosis (acute); onion-skin changes (chronic recurrent)
• Schistocytes visible in capillary lumina on biopsy